Immune cells associated with the intestinal epithelium comprise a variety of cell populations that can influence gastrointestinal infections, intestinal inflammation and inflammatory bowel diseases. We have recently identified a novel innate immune cell population, which we have called iCD8a cells, with important functions in mucosal immunity. iCD8a cells reside within the intestinal epithelium and are characterized by expression of CD8a homodimers. However, these cells lack TCR, NK1.1 and IL-7Ra expression and are thus distinct from intraepithelial lymphocytes and previously identified subsets of innate lymphoid cells. Our preliminary analysis suggests that this novel immune cell population is more closely related to the lymphoid than the myeloid lineage of immune cells. Moreover, our initial analysis of the cytokine expression profile and effector functions of iCD8a cells indicates that they belong to the innate branch of the immune system. Additionally, we have obtained preliminary evidence that iCD8a cells can influence intestinal inflammation induced by agonistic antibodies directed against the co-stimulatory molecule CD40, and colitis induced by infection with the intestinal pathogen Citrobacter rodentium. Finally, we have shown the presence of cells with a phenotype similar to murine iCD8a cells in the intestinal epithelium of human subjects. Guided by these preliminary studies we have formulated the original hypothesis that iCD8a cells are a novel innate-type lymphoid population with a regulatory role in infections and inflammatory diseases of the gastrointestinal tract. We will test this hypothesis is three specific aims: Specifc Aim 1 will characterize the lineage development of iCD8a cells, to provide further evidence that these cells are derived from lymphoid progenitors and are distinct from all previously described innate lymphocyte subsets; Specific Aim 2 will explore the effector functions of iCD8a cells, including their interactions with mucosal epithelial cells and other immune cells; and Specific Aim 3 will assess the contribution of iCD8a cells to intestinal inflammation and colitis in mice induced by anti-CD40 antibodies or C. rodentium infection. The long-term goal of this research is to explore iCD8a cells as novel therapeutic targets for infectious and inflammatory disorders of the gastrointestinal tract.